Department of Neurosurgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan.
Brain Res Bull. 2011 Nov 25;86(5-6):334-9. doi: 10.1016/j.brainresbull.2011.09.015. Epub 2011 Sep 25.
Levetiracetam (LEV) inhibits partial refractory epilepsy in human, and both convulsive and absence-like seizures in the spontaneously epileptic rat (SER). Two-thirds of hippocampal CA3 neurons in SER show a long-lasting depolarization shift, with accompanying repetitive firing upon mossy fiber stimulation. This abnormal excitability is probably attributable to abnormalities in the L-type Ca(2+) channels. We performed electrophysiological studies to elucidate the mechanism underlying the antiepileptic effects of LEV via intracellular recording from the hippocampal CA3 neurons in slice preparations of SER and non-epileptic Wistar rats. LEV (100 μM) inhibited the depolarization shift with repetitive firing by mossy fiber stimulation (MFS), without affecting the first spike in SER CA3 neurons. At a higher dose (1mM), LEV suppressed the first spike in all SER neurons (including the CA3 neurons which showed only a single action potential by MFS), while the single action potential of Wistar rat CA3 neurons remained unaffected. SER CA3 neurons with MFS-induced abnormal firing exhibited a higher number of repetitive spikes when a depolarization pulse was applied in the SER CA3 neurons. LEV (100 μM, 1mM) reduced the repetitive firing induced by a depolarization pulse applied without affecting Ca(2+) spike in SER neurons. LEV is known not to bind glutamate and gamma-aminobutyric acid (GABA) receptors. These findings suggest that the therapeutic concentration of LEV inhibits abnormal firing of the CA3 neurons by modulating abnormal synaptic transmission and abnormal Na(+) channels in SER.
左乙拉西坦（LEV）抑制人类部分难治性癫痫，以及自发性癫痫大鼠（SER）的惊厥和类似失神发作。SER 的三分之二海马 CA3 神经元表现出持久的去极化漂移，伴随着苔藓纤维刺激时的重复放电。这种异常兴奋性可能归因于 L 型钙（Ca2+）通道的异常。我们通过 SER 和非癫痫 Wistar 大鼠切片海马 CA3 神经元的细胞内记录进行电生理研究，以阐明 LEV 的抗癫痫作用机制。LEV（100μM）抑制苔藓纤维刺激（MFS）引起的去极化漂移和重复放电，而不影响 SER CA3 神经元的第一个尖峰。在较高剂量（1mM）下，LEV 抑制所有 SER 神经元（包括仅通过 MFS 表现出单个动作电位的 CA3 神经元）的第一个尖峰，而 Wistar 大鼠 CA3 神经元的单个动作电位不受影响。在 SER CA3 神经元中，当施加去极化脉冲时，MFS 诱导异常放电的 CA3 神经元表现出更多的重复尖峰。LEV（100μM，1mM）减少了在不影响 SER 神经元 Ca2+尖峰的情况下施加去极化脉冲引起的重复放电。LEV 已知不与谷氨酸和γ-氨基丁酸（GABA）受体结合。这些发现表明，LEV 的治疗浓度通过调节 SER 中的异常突触传递和异常钠（Na+）通道来抑制 CA3 神经元的异常放电。
